Ottawa Hospital Research Institute, Center for Cancer Therapeutics, Ottawa, Ontario, Canada.
Clin Cancer Res. 2013 Jul 15;19(14):3832-43. doi: 10.1158/1078-0432.CCR-12-3199. Epub 2013 May 28.
Acute lymphoblastic leukemia (ALL) remains incurable in most adults. It has been difficult to provide effective immunotherapy to improve outcomes for the majority of patients. Rhabdoviruses induce strong antiviral immune responses. We hypothesized that mice administered ex vivo rhabdovirus-infected ALL cells [immunotherapy by leukemia-oncotropic virus (iLOV)] would develop robust antileukemic immune responses capable of controlling ALL.
Viral protein production, replication, and cytopathy were measured in human and murine ALL cells exposed to attenuated rhabdovirus. Survival following injection of graded amounts of ALL cells was compared between cohorts of mice administered γ-irradiated rhabdovirus-infected ALL cells (iLOV) or multiple control vaccines to determine key immunotherapeutic components and characteristics. Host immune requirements were assessed in immunodeficient and bone marrow-transplanted mice or by adoptive splenocyte transfer from immunized donors. Antileukemic immune memory was ascertained by second leukemic challenge in long-term survivors.
Human and murine ALL cells were infected and killed by rhabdovirus; this produced a potent antileukemia vaccine. iLOV protected mice from otherwise lethal ALL by developing durable leukemia-specific immune-mediated responses (P < 0.0001), which required an intact CTL compartment. Preexisting antiviral immunity augmented iLOV potency. Splenocytes from iLOV-vaccinated donors protected 60% of naïve recipients from ALL challenge (P = 0.0001). Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of iLOV. Similarly, injecting uninfected irradiated viable, apoptotic, or necrotic leukemia cells with/without concurrent rhabdovirus administration was ineffective.
Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia.
急性淋巴细胞白血病（ALL）在大多数成人中仍无法治愈。很难为大多数患者提供有效的免疫疗法来改善预后。弹状病毒可诱导强烈的抗病毒免疫反应。我们假设，给予体外感染的弹状病毒 ALL 细胞的小鼠（通过白血病致癌病毒（iLOV）进行免疫治疗）将产生强大的抗白血病免疫反应，能够控制 ALL。
在暴露于减毒弹状病毒的人源和鼠源 ALL 细胞中测量病毒蛋白的产生、复制和细胞病变作用。通过比较接受 γ 射线照射的感染了弹状病毒的 ALL 细胞（iLOV）或多种对照疫苗处理的小鼠亚群中注射分级 ALL 细胞后的存活率，确定关键的免疫治疗成分和特征。通过免疫缺陷和骨髓移植小鼠或通过从免疫供体中过继性转移脾细胞来评估宿主免疫需求。通过长期幸存者的第二次白血病挑战来确定抗白血病免疫记忆。
人源和鼠源 ALL 细胞均被弹状病毒感染和杀伤；这产生了一种有效的抗白血病疫苗。iLOV 通过产生持久的白血病特异性免疫介导的反应（P < 0.0001）来保护小鼠免受致命的 ALL，这需要完整的 CTL 区室。预先存在的抗病毒免疫增强了 iLOV 的效力。来自 iLOV 疫苗接种供体的脾细胞可保护 60%的未致敏受者免受 ALL 挑战（P = 0.0001）。注射由多种 Toll 样受体激动剂激活的白血病细胞或同时注射这些细胞，不能重现 iLOV 的保护作用。同样，注射未感染的照射存活、凋亡或坏死白血病细胞，无论是否同时给予弹状病毒，均无效。
感染弹状病毒的白血病细胞可用于产生疫苗，该疫苗可诱导针对侵袭性白血病的强大特异性免疫。
